Process of making c unsaturated ketone related to vitamin a



Patented Oct. 10, 1950 PROCESS OF MAKING C13 UN SATURATED KETONE RELATEDTO VITAMIN A David Adriaan van Dorp and Josef Ferdinand Arens, Oss,Netherlands, assignors to Organon, Inc., Orange, .N 3., a corporation ofNew Jersey No Drawing. Application February 5, 1946, Serial No. 645,699.In the Netherlands Septemher 7, 1945 X stands for an unsaturatedhydrocarbon group containing a carbon chain in which double bonds arearranged in such a way, that a continuous series of conjugated doublebonds exists between those in R and the one in the C=O- R1 is an alkylgroup, preferably a methyl group.

The following three ketones will be described in the examples, althoughthe invention is not limited ithereto which we shall designate as theCue-ketone;

designated as the Gig-ketone;

designated as the Czl-iketone.

A compound to which was assigned the structure of the Cit-ketone(Formula 1) has been described by Karrer et al., who condensed the acidchloride of ionylidene acetic acid with methyl zinc iodide (Helv. Chim.Acta 17, 3 (1934)). Their product has an odour similar to that of,d-ionone, and does not yield a crystalline semicarbazone. Our productis practically odorless, and gives a crystalline semicarbazone. M. P.159.5, l60.5 C.

Probably Karrers product was a mixture of several isomers, as the acidchloride was prewith ethyl bromoacetate and subsequent saponification.Although there may have been some genuine Cm-ketone in Karrers product,there is no proof that this was in fact the case.

A compound of the supposed structure of Formula 2 has been described byHeilbron and co-workers (J. Chem. ,Soc. 1936, 561). Their compoundcrystallizes and melts at 144 C. which is improbably high for a ketonefrom this group. By condensation with ethyl bromoacetate and zinc theyconverted their product into an ester which was devoid of vitamin Aactivity. Also the acid was not active.

Our ketone is a thick yellow oil. Condensation with ethyl bromoacetateyields an ester which has a very strong biological activity. Also theacid is very active (0. f. copending application No. 645,698), nowabandoned.

It follows therefore, that Heilbrons synthesis of the Cw-ketone wasfallacious. This is further borne out by Heilbrons own statement, thathis starting material, thought to be ,B-ionylidene ethanal (R=CH-CHO),had an absorption spectrum entirely different from that expected, and soit must be concluded that his material was a different compound (seeHeilbron in Vitamines and Hormones, 1944., p. 180).

Our ketones have been obtained from the acids R=XCOOH, in which R."fi-ionylidene group or a group which may be easily converted into theB-ionylidene group, and X has the same meaning as above, by reacting theacid or a functional derivative thereof, such as a halogenide, an ester,the amide, the nitrile, a salt, etc. with an organo-metal1ic compound.As such we used a methyl magnesium halogenide and methyl lithium, butothers may be used as well.

The following examples may serve as an illustration ofv the invention.It is to be understood, however, that the invention is not limitedthereto, but may be varied within the scope of the appended claim.

Into a 500 cc. round bottomed flask, provided with mechanical stirrer,dropping funnel, reflux condenser and gas inlet tube, 4.6 g. of finelycu lithium and cc. of absolute ether are introduced while passingthrough pure nitrogen gas. Then a solution of 4'7 g. of methyliodide in100 cc. of abs. ether is added in about 3 hours. The stirring iscontinued for an hour, after which the mixture is diluted with 200 cc.of abs. ether and left for sedimentation during 15 minutes.

represents the The solution of methyl 1ithium, which is obtained, ispressed by way of a syphon filled up with glass wool for filteringpurposes into a second flask, which has been previously filled withnitrogen gas and which has a capacity of 2 liters and is likewiseIPI'OVidEd with a mechanical stirrer, dropping funnel, reflux condenserand gas inlet tube.

To the clear methyl lithium solution a solution of 22.0 g. of ionylideneacetic acid (obtained by Reformatzky condensation of p-ionone with ethylbromoacetate under the influence of zinc, followed by dehydration withanhydrous oxalic acid and saponification.) in 800 cc. of abs. ether isslowly added. A reaction immediately sets in. After decomposition withice water, drying and evaporation of the ether layer the residue isdistilled in vacuo, after which 16.5 g. of a yellow oil, boiling between90 and 100 C./0.001 m. m. are obtained. It is a ketone with the generalformula Ciel-I240, which corresponds to the structural formula It ispurified via the semicarbazone. The r covered pure ketone after vacuumdistillation is a pale yellow oil, B. P. 104-107 C./0.01 m. m.

The semicarbazone melts at 159.5-160.5C.and has 3, A max=310 mp.

Example 2.Cm-ketohe by condensation of ionylidene crotonic acid withmethyl lithium As in Example 1 a solution of methyl ithium is prepared.To this a solution of 23.0 g. of crystalline ionylidene crotonic acid(obtained by Reformatzky condensation of B-ionone with methyl'y-bromocrotonate under the influence of zinc, followed bysaponification of the dehydrated ester) in 900 cc. of abs. ether isadded, While stirring, in about minutes. The reaction is instantaneous.The reaction product is decomposed with ice water. The ether layer iswashed till free from alkali, dried with anhydrous sodium sulphate,after which the etheris distilled off. As a residue 23 g. of thepractically pure Cm-ketone is obtained. The empirical formula of thisketone iSCisHzeO and the structural formula It is a pale'yellowliquid,-boiling between 137 and 140 C. at a pressure of 0.01 m. m. whichwith semicarbazide gives a very pale yellow semican bazone, M. P.188.6-189.6 C. (corr.), and Amax 34:7 my. 7

Example 3.C1g-ketone by condensation of ionylidene crotonamide withmethyl magnesium bromide To a solution of methyl magnesium bromide,which has been prepared from 6.0 g. of magnesium, in 100 cc. of dibutylether a solution of 28 g. of ionylidene crotonamide, prepared byreacting 4 methyl ionylidene crotonate with ammonia) in dibutyl other isadded. The mixture is heated in an atmosphere of nitrogen under refluxuntil the Gilman test (vide J. Am. Chem. Soc. 47, 2406 (1925)) toGrignard compounds has become negative.

The reaction mixture is poured out on ice and diluted hydrochloric acid,the ether layer is separated, washed with water, sodium bicarbonatesolution and again with water. After drying with anhydrous sodiumsulphate the ether is distilled off in vacuo. The residue is treatedwith Girard reagent P and the ketonic fraction is distilled in a highvacuum. The same product as described in Example 2 is obtained.

In an analogous way as described in Example 2 the ketone C21H30O, whichpossesses the structural formula is obtained by reacting vitamin A acidwhich has the structural formula of vitamin A except that the methanolgroup is replaced by a carboxyl group, (the preparation of which isdescribed in the copending application No. 645,698) with methyl lithium.

The ketone 021E300 is a yellow oil, forming a semicarbazone which meltsat -19l C. (corn). The ketone, when biologically tested, possessesvitamin A activity.

What we claim is:

A process for the manufacture of the unsaturated ketone having thestructural formula comprisin reacting said compound with methyl lithium,and thereafter hydrolyzing the resulting addition product.

DAVID ADRIAAN VAN DORP. JOSEF FERDINAND ARENS.

REFERENCES CITED The following references are of record in the file ofthis patent:

Karrer et al., Helv. Chim. Acta 17, 3-7 (1934). Heilbron et al., Jour.Chem. Soc., London, 1936,

I-Ieilbron et al., J our. Chem. Soc, London, 1939,

Heilbron et al., Chem. Soc. Jour. (1942), pages

